Kidney Cancer. We have identified the tumor suppressor gene for the familial form of kidney cancer associated with von Hippel Lindau disease and have results to conclusion that this gene is also the rate limiting gene for sporadic clear cell kidney cancer. Tumor suppressor gene. This was accomplished by performing genetic studies in members of kindreds affected with this familial cancer syndrome. Genetic linkage analysis localized the VHL gene to a small region of chromosome 3. The region of the VHL gene was cloned and a genetic and physical map of the region were constructed. By analyzing the cloned DNA from the defined region, a candidate VHL tumor suppressor gene was identified. Mutational analysis of this conserved gene identified germline mutations in the VHL gene in affected individuals from 85/114 kindred. resulting in amino acid deletions, frameshift and/or other changes. A definite correlation has been identified between the location and type of VHL mutations and the phenotype of the disease; missense mutations were identified in the germline of families in which pheochromocytoma developed. In order to determine if the VHL gene is the critical, rate limiting gene for kidney cancer, VHL gene analysis of cell lines and tumor tissue from patients with sporadic, non-familial kidney cancer was performed. VHL mutations were identified in 57% of clear cell renal carcinomas analyzed and LOH was observed in 98% of those samples. The discovery of VHL mutations in a majority of localized as well as advanced renal carcinomas indicates that the VHL gene plays a critical, rate limiting role in the origin of both sporadic and hereditary kidney cancer. Prostate carcinoma. A program has been initiated that is designed to identify tumor suppressor genes that are involved in the development and/or progression of prostate cancer. Loss of heterozygosity studies are being performed on matched samples of normal and tumor DNA to map regions of the genome that are frequently lost during tumor development. A region from the short arm of chromosome 8 (8p22) has been shown to be lost frequently in prostate tumors. Candidate cDNAs are being cloned from this region to be evaluated as potential tumor suppressor genes. We are also evaluating the antitumor effect of thymidine kinase or cytosine deaminase gene modified prostate cancer cells followed by treatment ganciclovir or 5FU. The significance of this project lies in the identification of the tumor suppressor genes associated with kidney and prostate cancer as well as in the evaluation and development of new agents for use in therapy of patients with these neoplasms.